EP3386509A1 - Use of agonists of type-2 dopaminergic receptors in treatment of conditions caused by elevated vascular endothelial growth factor levels - Google Patents
Use of agonists of type-2 dopaminergic receptors in treatment of conditions caused by elevated vascular endothelial growth factor levelsInfo
- Publication number
- EP3386509A1 EP3386509A1 EP16831636.2A EP16831636A EP3386509A1 EP 3386509 A1 EP3386509 A1 EP 3386509A1 EP 16831636 A EP16831636 A EP 16831636A EP 3386509 A1 EP3386509 A1 EP 3386509A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- cabergoline
- treatment
- growth factor
- vascular endothelial
- eye
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 title claims abstract description 38
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 title claims abstract description 35
- 230000003291 dopaminomimetic effect Effects 0.000 title claims abstract description 17
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 title claims abstract 7
- 239000000556 agonist Substances 0.000 title description 8
- 229960004596 cabergoline Drugs 0.000 claims abstract description 43
- KORNTPPJEAJQIU-KJXAQDMKSA-N Cabaser Chemical compound C1=CC([C@H]2C[C@H](CN(CC=C)[C@@H]2C2)C(=O)N(CCCN(C)C)C(=O)NCC)=C3C2=CNC3=C1 KORNTPPJEAJQIU-KJXAQDMKSA-N 0.000 claims abstract description 41
- 210000004204 blood vessel Anatomy 0.000 claims abstract description 31
- 230000035699 permeability Effects 0.000 claims abstract description 22
- 210000001525 retina Anatomy 0.000 claims abstract description 18
- 208000030533 eye disease Diseases 0.000 claims abstract description 16
- 230000033115 angiogenesis Effects 0.000 claims abstract description 11
- 239000000018 receptor agonist Substances 0.000 claims abstract description 8
- 229940044601 receptor agonist Drugs 0.000 claims abstract description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
- 201000010099 disease Diseases 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 101150049660 DRD2 gene Proteins 0.000 abstract description 8
- 230000006806 disease prevention Effects 0.000 abstract description 2
- 102100039037 Vascular endothelial growth factor A Human genes 0.000 description 31
- 241001465754 Metazoa Species 0.000 description 15
- 210000001519 tissue Anatomy 0.000 description 15
- 230000004378 blood-retinal barrier Effects 0.000 description 13
- 208000004644 retinal vein occlusion Diseases 0.000 description 13
- 208000005590 Choroidal Neovascularization Diseases 0.000 description 10
- 206010060823 Choroidal neovascularisation Diseases 0.000 description 10
- 206010012689 Diabetic retinopathy Diseases 0.000 description 9
- 201000005667 central retinal vein occlusion Diseases 0.000 description 9
- 206010012601 diabetes mellitus Diseases 0.000 description 9
- 208000002780 macular degeneration Diseases 0.000 description 9
- 108020003175 receptors Proteins 0.000 description 9
- 102000005962 receptors Human genes 0.000 description 9
- 206010064930 age-related macular degeneration Diseases 0.000 description 8
- 210000004155 blood-retinal barrier Anatomy 0.000 description 8
- 238000012014 optical coherence tomography Methods 0.000 description 8
- 201000004569 Blindness Diseases 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- 206010012688 Diabetic retinal oedema Diseases 0.000 description 6
- 201000011190 diabetic macular edema Diseases 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 206010030113 Oedema Diseases 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- 201000007527 Retinal artery occlusion Diseases 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 230000028327 secretion Effects 0.000 description 5
- 230000004393 visual impairment Effects 0.000 description 5
- 208000005623 Carcinogenesis Diseases 0.000 description 4
- 206010033266 Ovarian Hyperstimulation Syndrome Diseases 0.000 description 4
- 230000036952 cancer formation Effects 0.000 description 4
- 231100000504 carcinogenesis Toxicity 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 4
- 208000018769 loss of vision Diseases 0.000 description 4
- 231100000864 loss of vision Toxicity 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 230000001575 pathological effect Effects 0.000 description 4
- 230000035755 proliferation Effects 0.000 description 4
- 102000004127 Cytokines Human genes 0.000 description 3
- 108090000695 Cytokines Proteins 0.000 description 3
- 229920002307 Dextran Polymers 0.000 description 3
- 206010038934 Retinopathy proliferative Diseases 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 201000005849 central retinal artery occlusion Diseases 0.000 description 3
- 230000016087 ovulation Effects 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 230000002062 proliferating effect Effects 0.000 description 3
- 230000002207 retinal effect Effects 0.000 description 3
- 230000000638 stimulation Effects 0.000 description 3
- 206010003694 Atrophy Diseases 0.000 description 2
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 2
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 101000595923 Homo sapiens Placenta growth factor Proteins 0.000 description 2
- 206010021143 Hypoxia Diseases 0.000 description 2
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 2
- 102000000589 Interleukin-1 Human genes 0.000 description 2
- 108010002352 Interleukin-1 Proteins 0.000 description 2
- 102000004889 Interleukin-6 Human genes 0.000 description 2
- 108090001005 Interleukin-6 Proteins 0.000 description 2
- 206010025421 Macule Diseases 0.000 description 2
- 102100035194 Placenta growth factor Human genes 0.000 description 2
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 2
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 2
- 208000017442 Retinal disease Diseases 0.000 description 2
- 102000013275 Somatomedins Human genes 0.000 description 2
- 108010009583 Transforming Growth Factors Proteins 0.000 description 2
- 102000009618 Transforming Growth Factors Human genes 0.000 description 2
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 2
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 2
- 230000037444 atrophy Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 210000003161 choroid Anatomy 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 229940126864 fibroblast growth factor Drugs 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 230000007954 hypoxia Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 229940100601 interleukin-6 Drugs 0.000 description 2
- 230000005012 migration Effects 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 2
- 229960001052 streptozocin Drugs 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- 210000004127 vitreous body Anatomy 0.000 description 2
- BJHCYTJNPVGSBZ-YXSASFKJSA-N 1-[4-[6-amino-5-[(Z)-methoxyiminomethyl]pyrimidin-4-yl]oxy-2-chlorophenyl]-3-ethylurea Chemical compound CCNC(=O)Nc1ccc(Oc2ncnc(N)c2\C=N/OC)cc1Cl BJHCYTJNPVGSBZ-YXSASFKJSA-N 0.000 description 1
- 206010069729 Collateral circulation Diseases 0.000 description 1
- 102000004980 Dopamine D2 Receptors Human genes 0.000 description 1
- 108090001111 Dopamine D2 Receptors Proteins 0.000 description 1
- 206010014567 Empty Sella Syndrome Diseases 0.000 description 1
- 208000001287 Galactorrhea Diseases 0.000 description 1
- 206010017600 Galactorrhoea Diseases 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 102100032742 Histone-lysine N-methyltransferase SETD2 Human genes 0.000 description 1
- 101000654725 Homo sapiens Histone-lysine N-methyltransferase SETD2 Proteins 0.000 description 1
- 102000018071 Immunoglobulin Fc Fragments Human genes 0.000 description 1
- 108010091135 Immunoglobulin Fc Fragments Proteins 0.000 description 1
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 1
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 208000035719 Maculopathy Diseases 0.000 description 1
- 208000019255 Menstrual disease Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 208000007913 Pituitary Neoplasms Diseases 0.000 description 1
- 201000005746 Pituitary adenoma Diseases 0.000 description 1
- 206010061538 Pituitary tumour benign Diseases 0.000 description 1
- 102100040681 Platelet-derived growth factor C Human genes 0.000 description 1
- 102000003946 Prolactin Human genes 0.000 description 1
- 108010057464 Prolactin Proteins 0.000 description 1
- 208000005793 Restless legs syndrome Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- 101710105463 Snake venom vascular endothelial growth factor toxin Proteins 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 108010073925 Vascular Endothelial Growth Factor B Proteins 0.000 description 1
- 108010073923 Vascular Endothelial Growth Factor C Proteins 0.000 description 1
- 108010073919 Vascular Endothelial Growth Factor D Proteins 0.000 description 1
- 108010053096 Vascular Endothelial Growth Factor Receptor-1 Proteins 0.000 description 1
- 108010053100 Vascular Endothelial Growth Factor Receptor-3 Proteins 0.000 description 1
- 102100038217 Vascular endothelial growth factor B Human genes 0.000 description 1
- 102100038232 Vascular endothelial growth factor C Human genes 0.000 description 1
- 102100038234 Vascular endothelial growth factor D Human genes 0.000 description 1
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 description 1
- 102100033179 Vascular endothelial growth factor receptor 3 Human genes 0.000 description 1
- 208000000208 Wet Macular Degeneration Diseases 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 229960002833 aflibercept Drugs 0.000 description 1
- 108010081667 aflibercept Proteins 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 210000000416 exudates and transudate Anatomy 0.000 description 1
- 210000002503 granulosa cell Anatomy 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 208000031424 hyperprolactinemia Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000001365 lymphatic vessel Anatomy 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 210000001328 optic nerve Anatomy 0.000 description 1
- 229940127017 oral antidiabetic Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 210000002394 ovarian follicle Anatomy 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000009589 pathological growth Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000000649 photocoagulation Effects 0.000 description 1
- 208000021310 pituitary gland adenoma Diseases 0.000 description 1
- 108010017992 platelet-derived growth factor C Proteins 0.000 description 1
- 229960003089 pramipexole Drugs 0.000 description 1
- FASDKYOPVNHBLU-ZETCQYMHSA-N pramipexole Chemical compound C1[C@@H](NCCC)CCC2=C1SC(N)=N2 FASDKYOPVNHBLU-ZETCQYMHSA-N 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 201000002212 progressive supranuclear palsy Diseases 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 229940097325 prolactin Drugs 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 229960003876 ranibizumab Drugs 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 210000001957 retinal vein Anatomy 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 239000002525 vasculotropin inhibitor Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to use of type-2 dopaminergic receptor agonists in treatment of eye diseases caused by an elevated level of vascular endothelial growth factor (VEGF), particularly in treatment or prevention of retinal disorders resulting from an increase in permeability of blood vessels and their angiogenesis.
- VEGF vascular endothelial growth factor
- Eye diseases in which an increase in permeability of blood vessels and their angiogenesis occur, include a multitude of diseases, mainly of the retina, such as diabetic macular edema, diabetic retinopathy, age-related macular degeneration, retinal artery occlusion or retinal vein occlusion.
- Diabetic macular edema develops in patients with prolonged diabetes and more advanced presentation of diabetic retinopathy. It occurs in about 14% of diabetics. The frequency of DME occurrence is depends on stage of retinopathy and diabetes type and duration. After 25 years of diabetes DME occurs in about 30% of patients with type 1 and type 2 diabetes treated with insulin and in about 15% of patients with type 2 diabetes treated with oral anti-diabetic medication. Diabetic macular edema is defined by a presence of liquid or hard exudates within 1 dd (disc diameter of the optic nerve) from the center of the macula.
- Diabetic retinopathy is the most common cause of blindness in developed countries nowadays. It is the result of the increase in diabetes prevalence in those countries. According to WHO in the year 2002 diabetic retinopathy was the cause of blindness in 1 .8 million people (4.8%) worldwide. In USA, every year, it becomes the reason for the loss of vision for about 12-24 thousands of patients suffering from diabetes. From a clinical point of view DR has few variants, such as non-proliferative retinopathy, pre-proliferative retinopathy, diabetic maculopathy, proliferative retinopathy and advanced diabetic retinopathy. In most of these cases edema of the retina occurs and, in case of proliferative forms, proliferation of pathological blood vessels.
- Age-related macular degeneration is the main reason of the loss of vision in adults over 50 years old. It occurs in 8.8% of the population, more frequently in females, and its occurrence increases with age and it affects almost 28% of people over age 75. It affects 50 million people globally. Due to population ageing the problem of AMD increases and about 10% of people over 45 years old are endangered by the disease. The so-called dry form of AMD makes up 90% of AMD cases and causes atrophic lesions within the macula and gradual loss of vision. In 10% of patients with AMD the wet (exudative) AMD form occurs, which causes blood vessel carcinogenesis in retina and choroid (choroidal neovascularization; CNV) and leads to a rapid vision worsening or vision loss.
- CNV blood vessel carcinogenesis in retina and choroid
- Retinal artery occlusion or its branch occlusion, is a relatively rare condition. It is characterized by a rapid and pain-less loss of vision. In case of quick treatment a complete or partial recovery of the vision is achieved.
- One of the complications of the central retinal artery occlusion is the proliferation of pathological blood vessels in eye tissues.
- Retinal vein occlusion occurs when central retinal vein (central retinal vein occlusion - CRVO) or its branch (branch retinal vein occlusion - BRVO) is blocked. It leads to different kinds of vision degradation.
- CRVO and BRVO are the second most common vascular diseases of the retina. The form with ischemia is less common than the form without it.
- Retinal vein occlusions occur with incidence of about 2 cases per 1000 people over 40 years of age and more than 5 cases per 1000 people over 64 years of age.
- central retinal artery occlusion in case of retinal vein occlusion late complications are possible, involving carcinogenesis of pathological blood vessels in the retina and in other eye tissues e.g. in drainage angle or iris.
- VEGF vascular endothelial growth factor
- VEGF is a group of cytokines comprising a group of substances that include: VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, VEGF-F and PIGF (placental growth factor).
- the VEGF cytokines act through specific receptors. Currently a few of types thereof are known such as: VEGFR-1 , VEGFR-2, FLK-1 and VEGFR-3.
- VEGF binds with receptors, which triggers a cascade of chemical reactions, which finally lead to an increase in permeability of blood vessels and stimulation of proliferation and migration of epithelial cells of blood and lymphatic vessels. Migrating cells of the endothelium create tubular structures, which are the buds of new blood vessels.
- VEGF vascular endothelial growth factor
- pro-inflammatory cytokines such as interleukin 1 (IL-1 ) and interleukin 6 (IL-6), substances secreted by tissues during the course of hypoxia e. g. hypoxia-induced factor (HIF-1 ), other growth factors e. g. transforming growth factor (TGF), insulin-like growth factor (IGF), fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF).
- IL-1 interleukin 1
- IL-6 interleukin 6
- TGF transforming growth factor
- IGF insulin-like growth factor
- FGF fibroblast growth factor
- PDGF platelet-derived growth factor
- angiogenesis in eye tissues occurs mostly in low-oxygen supply conditions due to e. g. a decrease in blood flow or an increase in tissue demand for oxygen and in chronic tissue inflammation, when factors promoting secretion of VEGF are released.
- the blood vessels that are created in that way are responsible for the occurrence, inter alia, of collateral circulation in cardiac muscle, which plays a very important role in supporting correct tissue oxidation.
- VEGF vascular endothelial growth factor
- VEGF also stimulates formation of new vessels, which are characterized by high permeability, which further increases edema of surrounding tissues.
- Newly created blood vessels disturb the physiological layout and course of blood vessels in the retina and the choroid of the eye and grow into vessel-free spaces e. g. the vitreous body.
- the walls of blood vessels formed during angiogenesis are fragile, they often break and cause hemorrhages into the vitreous body.
- VEGF vascular endothelial growth factor
- VEGF vascular endothelial growth factor
- the present invention relates to a use of type2 dopaminergic receptor agonists such as cabergoline in treatment of eye diseases caused by an elevated level of VEGF in eye tissues, which leads to their edema and to formation of pathological blood vessels.
- the invention thus relates to a use of cabergoline and other agonists of a dopaminergic D2 receptor in treatment of eye diseases caused by an elevated level of vascular endothelial growth factor.
- the present invention also relates to a possibility of using cabergoline and other agonists of a dopaminergic D2 receptor in treatment of eye diseases caused by an elevated level of vascular endothelial growth factor, in particular of diseases of an eye retina caused by an increase in permeability of blood vessels and/or their angiogenesis.
- the invention also relates to a pharmaceutical composition containing as an active ingredient cabergoline or other agonists of a dopaminergic D2 receptor for use in treatment of eye diseases caused by an elevated level of vascular endothelial growth factor, in particular diseases of an eye retina caused by an increase in permeability of blood vessels and/or their carcinogenesis.
- the composition according to the invention is for oral administration.
- OHSS ovarian hyperstimulation syndrome
- Cabergoline having a structure according to the formula shown below, is a dopaminergic D2 receptor agonist.
- Cabergoline is used in treatment of disorders related to an excessive prolactin secretion (e. g. menstrual disorders, lack of ovulation, galactorrhea), pituitary adenoma, idiopathic hyperprolactinemia, empty sella syndrome.
- Cabergoline is used in treatment of the above mentioned disorders in doses from 0.5 mg once per day or from 0.25 mg to 4.5 mg once per week.
- Cabergoline is successfully used in prevention and treatment of OHSS as well, with a daily dose of 0.5 mg - 1 mg over 7-14 days since the stimulation of ovulation.
- Polish patent application P.343593 relates to use of cabergoline in treatment of a restless legs syndrome, while in polish patent applications P.344574, P.380898 and P.383475 use of cabergoline in combination with pramipexole for treatment of multiple systems atrophy, progressive supranuclear palsy and Parkinson's disease were described.
- the rats were injected intraperitoneally with streptozocin at a dose of 60 mg/kg b.w. After 30 days since administration of streptozocin blood glucose level was checked and only rats with the blood glucose levels of over 250 mg% were qualified for the experiment.
- the following parameters were assessed: permeability of blood-retinal barrier using the dextran method (BRB) and the thickness of the retina using optical coherence tomography (OCT).
- the research was conducted on an experimental model of Wistar strain rats. Central retinal vein occlusion was performed using a 532 nm laser.
- CNV choroidal neovascularization
- CNV Choroidal neovascularization
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Ophthalmology & Optometry (AREA)
- Physiology (AREA)
- Nutrition Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PL16831636T PL3386509T3 (en) | 2015-12-09 | 2016-12-09 | Use of cabergoline in the treatment of eye diseases caused by elevated vascular endothelial growth factor levels |
HRP20192256TT HRP20192256T1 (en) | 2015-12-09 | 2019-12-16 | Use of cabergoline in the treatment of eye diseases caused by elevated vascular endothelial growth factor levels |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PL415170A PL232974B1 (en) | 2015-12-09 | 2015-12-09 | Application of the dopaminergic receptors type 2 agonists in treatment of eye chronic diseases caused by the increased level of endothelium derivative cell growth factor |
PCT/IB2016/057483 WO2017098461A1 (en) | 2015-12-09 | 2016-12-09 | Use of agonists of type-2 dopaminergic receptors in treatment of conditions caused by elevated vascular endothelial growth factor levels |
Publications (2)
Publication Number | Publication Date |
---|---|
EP3386509A1 true EP3386509A1 (en) | 2018-10-17 |
EP3386509B1 EP3386509B1 (en) | 2019-09-18 |
Family
ID=57909808
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP16831636.2A Active EP3386509B1 (en) | 2015-12-09 | 2016-12-09 | Use of cabergoline in the treatment of eye diseases caused by elevated vascular endothelial growth factor levels |
Country Status (13)
Country | Link |
---|---|
US (2) | US20180360820A1 (en) |
EP (1) | EP3386509B1 (en) |
CN (1) | CN108472294B (en) |
CA (1) | CA3007953C (en) |
DK (1) | DK3386509T3 (en) |
ES (1) | ES2761875T3 (en) |
HR (1) | HRP20192256T1 (en) |
IL (1) | IL259903B (en) |
LT (1) | LT3386509T (en) |
PL (2) | PL232974B1 (en) |
PT (1) | PT3386509T (en) |
RU (1) | RU2698728C1 (en) |
WO (1) | WO2017098461A1 (en) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PL241086B1 (en) * | 2017-09-26 | 2022-08-01 | Oseka Maciej | Pergolide to be applied in treatment of eye diseases connected with increased level of vascular endothelial growth factor (VEGF) and the pergolid-containing pharmaceutical composition |
PL430675A1 (en) * | 2019-07-23 | 2021-01-25 | Osęka Maciej | Bromocriptine for the treatment of ocular diseases related to elevated levels of vascular endothelial growth factor (VEGF) and a pharmaceutical composition containing bromocriptine |
CN113082031A (en) * | 2021-03-09 | 2021-07-09 | 温州医科大学附属眼视光医院 | Application of dopamine D1 and D2 receptor nonselective agonist in preparation of drugs for treating pathological angiogenesis of eyes |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4526892A (en) * | 1981-03-03 | 1985-07-02 | Farmitalia Carlo Erba, S.P.A. | Dimethylaminoalkyl-3-(ergoline-8'βcarbonyl)-ureas |
US6114326A (en) * | 1998-03-27 | 2000-09-05 | Pharmacia & Upjohn Company | Use of cabergoline in the treatment of restless legs syndrome |
EA200300124A1 (en) * | 1998-05-15 | 2003-10-30 | Фармация Энд Апджон Компани | APPLICATION OF PRAMIPEXOL FOR THE TREATMENT OF POLYSYSTEM ATROPHY AND PROGRESSIVE SUPRANUKLEAR PARALICH |
US20070155770A1 (en) * | 2006-01-03 | 2007-07-05 | Cedars-Sinai Medical Center | Treatment of anoragasmia or delayed orgasm |
KR100923195B1 (en) * | 2006-04-04 | 2009-10-22 | 고려대학교 산학협력단 | Methods for modulating the development of dopamine neuron by the Dopamine D2 receptor and compositions thereof |
ATE535243T1 (en) * | 2007-05-11 | 2011-12-15 | Santen Pharmaceutical Co Ltd | PROPHYLACTIC OR THERAPEUTIC AGENT FOR POSTERIOR EYE DISEASE HAVING SELECTIVE NON-ERGOT-D2 RECEPTOR AGONIST AS THE ACTIVE INGREDIENT |
CN102791134B (en) * | 2009-12-04 | 2015-04-22 | 魄金莱默有限公司 | Method of using dopamine reuptake inhibitors and their analogs for treating diabetes symptoms and delaying or preventing diabetes-associated pathologic conditions |
-
2015
- 2015-12-09 PL PL415170A patent/PL232974B1/en unknown
-
2016
- 2016-12-09 DK DK16831636.2T patent/DK3386509T3/en active
- 2016-12-09 ES ES16831636T patent/ES2761875T3/en active Active
- 2016-12-09 WO PCT/IB2016/057483 patent/WO2017098461A1/en active Application Filing
- 2016-12-09 CN CN201680072556.9A patent/CN108472294B/en active Active
- 2016-12-09 LT LTEP16831636.2T patent/LT3386509T/en unknown
- 2016-12-09 PL PL16831636T patent/PL3386509T3/en unknown
- 2016-12-09 EP EP16831636.2A patent/EP3386509B1/en active Active
- 2016-12-09 US US16/060,517 patent/US20180360820A1/en not_active Abandoned
- 2016-12-09 CA CA3007953A patent/CA3007953C/en active Active
- 2016-12-09 PT PT168316362T patent/PT3386509T/en unknown
- 2016-12-09 RU RU2018124858A patent/RU2698728C1/en active
-
2018
- 2018-06-07 IL IL259903A patent/IL259903B/en active IP Right Grant
-
2019
- 2019-12-16 HR HRP20192256TT patent/HRP20192256T1/en unknown
-
2020
- 2020-03-31 US US16/836,168 patent/US11324740B2/en active Active
Also Published As
Publication number | Publication date |
---|---|
PL3386509T3 (en) | 2020-08-24 |
CN108472294A (en) | 2018-08-31 |
RU2698728C1 (en) | 2019-08-29 |
US11324740B2 (en) | 2022-05-10 |
US20200222387A1 (en) | 2020-07-16 |
ES2761875T3 (en) | 2020-05-21 |
PT3386509T (en) | 2019-12-30 |
WO2017098461A1 (en) | 2017-06-15 |
CA3007953C (en) | 2022-11-29 |
PL415170A1 (en) | 2017-06-19 |
US20180360820A1 (en) | 2018-12-20 |
LT3386509T (en) | 2020-01-27 |
IL259903B (en) | 2020-09-30 |
PL232974B1 (en) | 2019-08-30 |
EP3386509B1 (en) | 2019-09-18 |
DK3386509T3 (en) | 2019-12-16 |
IL259903A (en) | 2018-07-31 |
HRP20192256T1 (en) | 2020-03-06 |
CN108472294B (en) | 2021-07-13 |
CA3007953A1 (en) | 2017-06-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11324740B2 (en) | Use of agonists of type-2 dopaminergic receptors in treatment of conditions caused by elevated vascular endothelial growth factor levels | |
Pożarowska et al. | The era of anti-vascular endothelial growth factor (VEGF) drugs in ophthalmology, VEGF and anti-VEGF therapy | |
Barros et al. | The effects of the subconjunctival injection of bevacizumab (Avastin®) on angiogenesis in the rat cornea | |
RU2519739C2 (en) | Ophthalmological pharmaceutical compositions for neoangiogenic eye pathologies | |
JP6944958B2 (en) | Use of sirolimus for the treatment of exudative age-related macular degeneration with persistent edema | |
Algvere et al. | Visual improvement in central retinal vein occlusion (CRVO) following intravitreal injections of bevacizumab (Avastin®) | |
US20170224815A1 (en) | Method of Preventing and Treating Retinal Microvasculature Inflammation Using C-Met Signaling Pathway Inhibition | |
Abdullaev et al. | APPROACHES TO THE TREATMENT OF DIABETIC RETINOPATHY | |
WO2021068962A1 (en) | Polypeptide for diseases related to angiogenesis and lymphangiogenesis and use thereof | |
CN110327350B (en) | Application of dopamine D1 receptor antagonist SCH39166 in preparation of drugs for treating pathological angiogenesis of eyes | |
Jiang et al. | The efficacy and safety of intravitreal conbercept combined with mitomycin C augmented trabeculectomy for treating neovascular glaucoma | |
Elsayed | Comparisons of Ranibizumab Injection and Dexamethasone Implant in Macular Oedema Secondary to Central Retinal Vein Occlusion | |
AlZamil et al. | Efficacy and Safety of Primary Intravitreal 2 mg Aflibercept for Cystoid Macular Edema after Phacoemulsification | |
SHARM et al. | Clinical Utilisation of Bevacizumab and Patient Monitoring in Retinal Vein Occlusion and Diabetic Macular Edema | |
WO2021014372A1 (en) | Bromocriptine for use in treating eye diseases associated with elevated level of vegf and a pharmaceutical composition comprising bromocriptine | |
KALDIRIM et al. | Intravitreal Dexamethasone Implant in the Treatment of Pseudophakic Cystoid Macular Edema or Irvine-Gass Syndrome | |
Vangipuram et al. | Future Direction in Diabetic Eye Disease | |
US20200289480A1 (en) | Pergolide for use in the treatment of eye diseases associated with an elevated level of vascular endothelial growth factor (vegf) and pharmaceutical composition containing pergolide | |
Frank | Clinical Applications of Angiogenesis Research | |
Frank | Diabetic Retinopathy: Clinical Applications of Angiogenesis Research | |
WO2019231800A1 (en) | Anti-cgrp antibodies for treating menstrual-related migraines | |
Pacella et al. | Adverse events associated with intraocular injection of anti-VEGF (bevacizumab) in retinal vein ccclusion: a case report | |
Monica-Blanka et al. | Bevacizumab for Macular Edema in Branch and Central Retinal Vein Occlusion. | |
A AL-Laftah | RANIBIZUMAB MONOTHERAPY VERSUS COMBINED RANIBIZUMAB PLUS TRIAMCINOLONE FOR TREATING DIABETIC MACULAR EDEMA; EVALUATION AFTER SINGLE INJECTION | |
Smith et al. | The Use of Somatostatin Analogues in Diabetic Retinopathy |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: UNKNOWN |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE |
|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE |
|
17P | Request for examination filed |
Effective date: 20180709 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
AX | Request for extension of the european patent |
Extension state: BA ME |
|
DAV | Request for validation of the european patent (deleted) | ||
DAX | Request for extension of the european patent (deleted) | ||
GRAP | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOSNIGR1 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: GRANT OF PATENT IS INTENDED |
|
INTG | Intention to grant announced |
Effective date: 20190327 |
|
RAP1 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: OSEKA, MACIEJ |
|
RIN1 | Information on inventor provided before grant (corrected) |
Inventor name: OSEKA, MACIEJ |
|
GRAS | Grant fee paid |
Free format text: ORIGINAL CODE: EPIDOSNIGR3 |
|
GRAA | (expected) grant |
Free format text: ORIGINAL CODE: 0009210 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE PATENT HAS BEEN GRANTED |
|
AK | Designated contracting states |
Kind code of ref document: B1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
REG | Reference to a national code |
Ref country code: GB Ref legal event code: FG4D |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: EP |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R096 Ref document number: 602016021056 Country of ref document: DE |
|
REG | Reference to a national code |
Ref country code: AT Ref legal event code: REF Ref document number: 1180488 Country of ref document: AT Kind code of ref document: T Effective date: 20191015 |
|
REG | Reference to a national code |
Ref country code: IE Ref legal event code: FG4D |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: NV Representative=s name: REUTELER AND CIE S.A., CH |
|
REG | Reference to a national code |
Ref country code: DK Ref legal event code: T3 Effective date: 20191211 Ref country code: HR Ref legal event code: TUEP Ref document number: P20192256T Country of ref document: HR |
|
REG | Reference to a national code |
Ref country code: PT Ref legal event code: SC4A Ref document number: 3386509 Country of ref document: PT Date of ref document: 20191230 Kind code of ref document: T Free format text: AVAILABILITY OF NATIONAL TRANSLATION Effective date: 20191217 |
|
REG | Reference to a national code |
Ref country code: SE Ref legal event code: TRGR |
|
REG | Reference to a national code |
Ref country code: NL Ref legal event code: FP |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: BG Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20191218 |
|
REG | Reference to a national code |
Ref country code: NO Ref legal event code: T2 Effective date: 20190918 |
|
REG | Reference to a national code |
Ref country code: HR Ref legal event code: ODRP Ref document number: P20192256T Country of ref document: HR Payment date: 20191216 Year of fee payment: 4 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: RS Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20190918 Ref country code: AL Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20190918 |
|
REG | Reference to a national code |
Ref country code: HR Ref legal event code: T1PR Ref document number: P20192256 Country of ref document: HR |
|
REG | Reference to a national code |
Ref country code: EE Ref legal event code: FG4A Ref document number: E018527 Country of ref document: EE Effective date: 20191212 |
|
REG | Reference to a national code |
Ref country code: GR Ref legal event code: EP Ref document number: 20190403882 Country of ref document: GR Effective date: 20200318 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: RO Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20190918 |
|
REG | Reference to a national code |
Ref country code: SK Ref legal event code: T3 Ref document number: E 33380 Country of ref document: SK |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: FG2A Ref document number: 2761875 Country of ref document: ES Kind code of ref document: T3 Effective date: 20200521 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: SM Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20190918 Ref country code: IS Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200224 |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R097 Ref document number: 602016021056 Country of ref document: DE |
|
PLBE | No opposition filed within time limit |
Free format text: ORIGINAL CODE: 0009261 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT |
|
PG2D | Information on lapse in contracting state deleted |
Ref country code: IS |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: IS Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200119 |
|
26N | No opposition filed |
Effective date: 20200619 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: SI Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20190918 Ref country code: MC Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20190918 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LU Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20191209 |
|
REG | Reference to a national code |
Ref country code: HR Ref legal event code: ODRP Ref document number: P20192256 Country of ref document: HR Payment date: 20201125 Year of fee payment: 5 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: CY Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20190918 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: HU Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT; INVALID AB INITIO Effective date: 20161209 Ref country code: MT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20190918 |
|
REG | Reference to a national code |
Ref country code: HR Ref legal event code: ODRP Ref document number: P20192256 Country of ref document: HR Payment date: 20211202 Year of fee payment: 6 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: TR Payment date: 20211201 Year of fee payment: 6 Ref country code: HR Payment date: 20211202 Year of fee payment: 6 Ref country code: LT Payment date: 20211202 Year of fee payment: 6 Ref country code: EE Payment date: 20211202 Year of fee payment: 6 Ref country code: FI Payment date: 20211223 Year of fee payment: 6 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: LV Payment date: 20211202 Year of fee payment: 6 Ref country code: CH Payment date: 20211216 Year of fee payment: 6 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: MK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20190918 |
|
REG | Reference to a national code |
Ref country code: AT Ref legal event code: UEP Ref document number: 1180488 Country of ref document: AT Kind code of ref document: T Effective date: 20190918 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: NO Payment date: 20221205 Year of fee payment: 7 |
|
REG | Reference to a national code |
Ref country code: HR Ref legal event code: PBON Ref document number: P20192256 Country of ref document: HR Effective date: 20221209 |
|
REG | Reference to a national code |
Ref country code: LT Ref legal event code: MM4D Effective date: 20221209 |
|
REG | Reference to a national code |
Ref country code: EE Ref legal event code: MM4A Ref document number: E018527 Country of ref document: EE Effective date: 20221231 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LV Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20221209 |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PL |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LI Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20221231 Ref country code: EE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20221231 Ref country code: CH Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20221231 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LT Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20221209 Ref country code: HR Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20221209 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: SK Payment date: 20231205 Year of fee payment: 8 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: GR Payment date: 20231229 Year of fee payment: 8 Ref country code: GB Payment date: 20231203 Year of fee payment: 8 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: SE Payment date: 20231203 Year of fee payment: 8 Ref country code: PT Payment date: 20231207 Year of fee payment: 8 Ref country code: NL Payment date: 20231204 Year of fee payment: 8 Ref country code: IT Payment date: 20231227 Year of fee payment: 8 Ref country code: IE Payment date: 20231205 Year of fee payment: 8 Ref country code: FR Payment date: 20231203 Year of fee payment: 8 Ref country code: DK Payment date: 20231206 Year of fee payment: 8 Ref country code: DE Payment date: 20231206 Year of fee payment: 8 Ref country code: CZ Payment date: 20231205 Year of fee payment: 8 Ref country code: AT Payment date: 20231214 Year of fee payment: 8 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: PL Payment date: 20231204 Year of fee payment: 8 Ref country code: BE Payment date: 20231204 Year of fee payment: 8 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: ES Payment date: 20240108 Year of fee payment: 8 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: FI Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20221209 |